Oral general anesthetics and metabolitically resistant anticonvulsants

ABSTRACT

The present invention is directed to novel themisone derivative compounds that have been modified to prevent the formation of the toxic metabolite, 2-phenyl-acrylamide. Compositions comprising such derivative compounds have activity as anesthetics and as neuroprotective agents.

RELATED APPLICATIONS

This application is a national stage filing of International ApplicationNo. PCT/US02/11507, filed Apr. 15, 2002, which claims priority under 35USC §119(e) to U.S. Provisional Application Ser. No. 60/284,040, filedApr. 16, 2001, Ser. No. 60/333,603, filed Nov. 27, 2001 and Ser. No.60/354,181, filed Feb. 4, 2002, the disclosures of which areincorporated herein.

FIELD OF THE INVENTION

The present invention is directed to novel derivatives ofα-hydroxy-α-methylbenzeneacetamide (themisone), and the use of suchderivatives as therapeutic agents. More particularly, compositionscomprising the present themisone derivatives can be administered forreducing the incidence and severity of seizures and for use as a generalanesthetic.

BACKGROUND OF THE INVENTION

Many compositions are available for sedating patients or, in largerdosages, for inducing surgical anethesia in patients. These materialsare used alone or in combination with other agents, such as nitrousoxide, to induce narcosis and to raise the patients pain threshold sothat the patient can withstand surgical procedures. Likewise in smallerdoses, these materials can reduce anxiety and generally sedate thepatient. For example the following compounds are in general use assedative and anesthetic agents: thiopental sodium,5-allyl-1-methyl-5-(1-methyl-2-pentynyl) barbituric acid sodium salt(brevitol), 2-bromo-2-chloro-1,1,1-trifloroethane (halothane), and thelike.

Most anesthetic and sedative agents, in addition to their beneficialeffects, also lower certain body functions, such as respiration, bloodpressure and heart action. Lowered body functions may sometimes lead tocomplications, particularly in older patients and in patients sufferingfrom cardiac and vascular diseases and diseases of the kidneys andliver. Likewise, reduction in blood pressure may also lead tocirculatory insufficiency during the surgical procedures which, unlessalleviated, may do serious harm even to patients who have previouslyexhibited no signs of heart, kidney or liver disfunction.

General anesthesia, administered as an inhaled or intravenous agent, fora surgical operation involves analgesia, amnesia, loss of consciousness,motionlessness and abolition of autonomic responses. The mechanism ofaction is still not completely understood, but most general anestheticsact at multiple molecular sites. The potential mechanisms of anesthesiaaction include protein receptor, lipid and ion channels. As thesolubility of anesthetics increases in oil, so does the potency leadingto the lipid theory developed by Meyer and Overton. There is also acorrelation between anesthesia potency and the ability of the anestheticto inhibit the enzyme activity of the protein, for example in fireflyluciferase, a model used for studying anesthesia. In addition,potentiation of the inhibitory response, mediated by theneurotransmitter GABA (gamma-aminobutyric acid), dampens neuronalexcitability placing the GABA receptor as a potential receptor site foranesthetic action. GABA is the major mediator of inhibitory synaptictransmission, and a family of ligand-gated chloride channel proteins.Other theories include NMDA and ligand-gated ion channels as a receptor.There is sufficient evidence supporting the blockade of Na⁺ channels andthe activation of K⁺ channels.

The effects of anesthesia depend on the concentration at the site ofaction, although concentrations cannot be measured in the brain ofhumans, therefore the concentration in the blood or expired gas (forinhaled anesthetics) is evaluated. Current inhaled general anesthetics(including, halothane enflurane, nitrous oxide, desflurane, isofluraneand sevoflurane, shown below) have a low therapeutic index (usually2–3), hence the discovery of a new structural class would help in thedevelopment of safer anesthetics.

The present invention is directed to derivatives of themisone, that havebeen found to have anticonvulsant and anesthetic activity. Themisone,also known as Atrolactamide, was found in the 1950's to be a very potentanticonvulsant. The racemic mixture protected 4 out of 4 mice againstseizures at 250 mg/kg, however the compound was toxic (blood dyscrasias,rash). Applicants believe the toxicity of this compound results from theformation of 2-phenyl-acrylamide by an elimination reaction as shownbelow:

To prevent the formation of this potential metabolite in vivo,applicants have designed and synthesized derivatives of themisone thatprevent the elimination and potential formation of 2-phenyl-acrylamide,a potential toxic metabolite. These compounds have been found to exhibitboth anti-convulsant activity as well as anesthetic acitivity.Accordingly, one aspect of the present invention is directed to novelthemisone derivatives that are blocked from forming 2-phenyl-acrylamideand the use of such compounds for reducing the incidence and severity ofseizures and for use as a general anesthetic.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having a generalstructure selected from the group consisting of:

wherein R₁ is selected from the group consisting of H, halo, alkyl,haloalkyl, NH₂ and C₁–C₄ alkoxy; R₂ is H or alkyl; R₉ is optionallysubstituted aryl or haloalkyl; and n is an integer ranging from 1–3, andthe use of such compounds as a sedative/anaesthetic or an anticonvulsiveagent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting the partition coefficient, P (in log P) vsminimum alveolar concentration (MAC) and representing the anestheticeffects of the themisone derivatives (indicated by a reduction in thethreshold of Isoflurane anesthesia).

FIG. 2 is a table listing the data produced during anticonvulsanttesting of orally administered themisone and compound 17 in mice. Themodel examines the compound's ability to stop the spread of seizuresinduced by a maximal electroshock (MES) test, where corneal electrodeimplants are primed with a drop of electrolyte solution and anelectrical stimulus is delivered for 0.2 second.

FIG. 3 is a table listing the data produced during anticonvulsanttesting (using a subcutaneous metrazol test) of intraperitoneal, (i.p.)administered themisone and compound 17 in mice. The subcutaneousmetrazol test (scMet) is conducted using a convulsant dose ofpentylenetetrazol at the peak effect time of the compound.

FIG. 4 is a table listing the data produced from a toxicity test (TOX).The animals walk on a spinning rod for varying lengths of time to checkfor the loss of righting reflex or other toxic effects.

FIG. 5 is a table listing the MES ED₅₀, ScMet ED₅₀ and Rotorod TD₅₀values for mice orally administered either compound 17 or phenytoid.

FIG. 6 is a graph plotting the heart rate vs dose and representing theeffects of the presence or absence of ICM-I-40N (17) on heart rateduring Isoflurane anesthesia.

FIG. 7 is a graph plotting the mean blood pressure vs dose andrepresenting the effects of the presence or absence of ICM-I-40N (17) onblood pressure during Isoflurane anesthesia.

FIG. 8 is a graph plotting the percent MAC reduction vs dose andrepresenting the reduction in the threshold of Isoflurane anesthesiafollowing the administration of ICM-I-40N (●), ICM-1-76D (◯), ICM-1-22(▪) and ICM-1-135 (□).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In describing and claiming the invention, the following terminology willbe used in accordance with the definitions set forth below.

As used herein, the term “purified” and like terms relate to theisolation of a molecule or compound in a form that is substantially freeof contaminants normally associated with the molecule or compound in anative or natural environment.

As used herein, the term “treating” includes prophylaxis of the specificdisorder or condition, or alleviation of the symptoms associated with aspecific disorder or condition and/or preventing or eliminating saidsymptoms.

As used herein, the term “halogen” means Cl, Br, F, and I. Especiallypreferred halogens include Cl, Br, and F. The term “haloalkyl” as usedherein refers to a C₁–C_(n) alkyl radical bearing at least one halogensubstituent, for example, chloromethyl, fluoroethyl or trifluoromethyland the like.

The term “C₁–C_(n) alkyl” wherein n is an integer, as used herein,represents a branched or linear alkyl group having from one to thespecified number of carbon atoms. Typically C₁–C₆ alkyl groups include,but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The term “C₂–C_(n) alkenyl” wherein n is an integer, as used herein,represents an olefinically unsaturated branched or linear group havingfrom 2 to the specified number of carbon atoms and at least one doublebond. Examples of such groups include, but are not limited to,1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl,and the like.

The term “C₂–C_(n) alkynyl” wherein n is an integer refers to anunsaturated branched or linear group having from 2 to the specifiednumber of carbon atoms and at least one triple bond. Examples of suchgroups include, but are not limited to, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 1-pentynyl, and the like.

The term “C₃–C_(n) cycloalkyl” wherein n is an integer refers to cyclicnon-aryl group, for example C₃–C₈ cycloalkyl, represents cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “lower alkyl” as used herein refers to branched or straightchain alkyl groups comprising one to eight carbon atoms, includingmethyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and thelike.

As used herein, the term “optionally substituted” refers to from zero tofour substituents, wherein the substituents are each independentlyselected. Each of the independently selected substituents may be thesame or different than other substituents.

As used herein the term “aryl” refers to a mono- or bicyclic carbocyclicring system having one or two aromatic rings including, but not limitedto, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, andthe like. “Optionally substituted aryl” includes aryl compounds havingfrom zero to four substituents, and “substituted aryl” includes arylcompounds having one to three substituents. The term (C₅–C₈ alkyl)arylrefers to any aryl group which is attached to the parent moiety via thealkyl group.

The term “heterocyclic group” refers to a mono- or bicyclic carbocyclicring system containing from one to three heteroatoms wherein theheteroatoms are selected from the group consisting of oxygen, sulfur,and nitrogen.

As used herein the term “heteroaryl” refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings containing fromone to three heteroatoms and includes, but is not limited to, furyl,thienyl, pyridyl and the like.

The term “bicyclic” represents either an unsaturated or saturated stable7- to 12-membered bridged or fused bicyclic carbon ring. The bicyclicring may be attached at any carbon atom which affords a stablestructure. The term includes, but is not limited to, naphthyl,dicyclohexyl, dicyclohexenyl, and the like.

As used herein, the term “pharmaceutically acceptable carrier”encompasses any of the standard pharmaceutical carriers, such as aphosphate buffered saline solution, water and emulsions such as anoil/water or water/oil emulsion, and various types of wetting agents.

As used herein, “effective amount” means an amount sufficient to producea selected effect. For example, an effective amount of an anticonvulsantthemisone derivative is an amount of the compound sufficient to reducethe incidence of seizures in a patient receiving the dose amount.

The term, “parenteral” means not through the alimentary canal but bysome other route such as subcutaneous, intramuscular, intraspinal, orintravenous.

As used herein the term “neurological disease” or “neurologicalcondition” includes neurological related maladies such as spasticity,seizures, depression or mood disorders, neuropathic pain, Alzheimer'sDisease, Parkinson's Disease, HIV Dementia and neurological disordersthat involve excessive activation of the N-methyl-D-aspartate (NMDA)receptor.

Compounds of the present invention that have one or more asymmetriccarbon atoms may exist as the optically pure enantiomers, or opticallypure diastereomers, as well as mixtures of enantiomers, mixtures ofdiastereomers, and racemic mixtures of such stereoisomers. The presentinvention includes within its scope all such isomers and mixturesthereof.

The MAC value is the minimum alveolar concentration of anesthetic at 1atm that produces immobility in 50% of the subjects.

The Invention

Previously in the 1950's atrolactamide (themisone) was tested as ananticonvulsant. This compound was found to have anticonvulsant activitybut was toxic (blood dyscrasias, rash). Based on applicant's believethat the toxicity of these compounds derived from the formation of themetabolite 2-phenyl-acrylamide, the novel themisone-related compounds ofthe present invention were prepared that are blocked from the formationof 2-phenyl-acrylamide. With that in mind compound ICM-I-40N (17) wassynthesized and evaluated for anticonvulsant activity.

The themisone derivatives of the present invention exhibit similaractivities to themisone without the risk of the toxicities associatedwith themisone administration. Furthermore, applicants have discoveredthat the themisone derivatives of the present invention also haveactivity as anesthetics.

In accordance with one embodiment the novel themisone derivatives of thepresent invention have the general structure:

wherein W is selected from the group consisting of alkyl, alkenyl,alkynyl optionally substituted aryl, and optionally substitutedheteroaryl;

Z is hydroxy, alkoxy, —OCOR₁₂, or, —COR₁₂;

R₁ is selected from the group consisting of H, halo, C₁–C₄ haloalkyl,—NH₂, hydroxy, and C₁–C₄ alkoxy;

R₃ is aryl, carboxyl, haloalkyl or —(C₁–C₄ alkyl)NHR₄, —CONR₁₀R₄ or H;

R₄ is selected from the group consisting of C₁–C₄ alkyl, aryl and H;

R₁₀ is H or C₁–C₄ alkyl;

R₉ is optionally substituted aryl or haloalkyl;

R₁₂ is C₁–C₄ alkyl, NH₂ or aryl;

m is an integer ranging from 0–3; and

n is an integer ranging from 0–1.

More particularly, the present invention is directed to a compoundrepresented by a formula selected from the group consisting of:

wherein R₁ and R₁₅ are independently selected from the group consistingof H, halo, C₁–C₄ haloalkyl, —NH₂, hydroxy, and C₁–C₄ alkoxy;

Z is hydroxy or alkoxy;

R₃ is aryl, carboxyl, haloalkyl, —(C₁–C₄ alkyl)NHR₄, —CONR₁₀R₄ or H;

R₄ is selected from the group consisting of C₁–C₄ alkyl, aryl and H;

R₅ and R₁₀ are independently H or C₁–C₄ alkyl, or R₁₀ and R₅ takentogether, can form with the adjacent ring, an optionally substituted 5-or 6-membered heterocyclic ring;

R₆, R₇ and R₈ are independently halo;

R₉ is optionally substituted aryl or haloalkyl;

m is an integer ranging from 0–1; and

n is an integer ranging from 0–1.

In accordance with one preferred embodiment the themisone derivedcompound has the general structure:

wherein R₁ is H or halo;

R₁₀ and R₅ are independently H, C₁–C₄ alkyl, or R₁₀ and R₅ takentogether, can form with the adjacent ring, an optionally substituted 5-or 6-membered heterocyclic ring;

R₄ is selected from the group consisting of C₁–C₄ alkyl, aryl and H;

R₆, R₇ and R₈ are independently halo; and

n is an integer ranging from 0–1. More preferably, R₁ is halo, R₁₀, R₄and R₅ are H, n is 0; and R₆, R₇ and R₈ are independently selected fromthe group consisting of F, Cl and Br. In one preferred embodiment the R₁substituent is in the meta or para position and R₆, R₇ and R₈ are eachF.

In one embodiment the themisone derivative compound has the generalstructure:

wherein R₁ is H or halo; and R₆, R₇ and R₈ are independently selectedfrom the group consisting of F, Cl and Br.

In an alternative embodiment, the themisone derived compound isrepresented by the formula

wherein R₁₁ is selected from the group consisting of C₁–C₄ alkyl, aryland H; and R₆, R₇ and R₈ are independently fluorine or chlorine. In onepreferred embodiment, R₁₁ is H or C₁–C₄ alkyl and R₆, R₇ and R₈ are eachfluorine

In accordance with one embodiment the themisone derivatives of thepresent invention can be formulated as pharmaceutical compositions bycombining the compounds with one or more pharmaceutically acceptablecarriers, fillers, solubilizing agents and stabilizers known to thoseskilled in the art. Such pharmaceutical compositions can be utilized asanalgesics, sedatives, anesthetics or as anticonvulsants.

Pharmaceutical compositions comprising the themisone derivatives of thepresent invention are administered to an individual in need thereof byany number of routes including, but not limited to, topical, oral,intravenous, intramuscular, intra-arterial, intramedullary, intrathecal,intraventricular, transdermal, subcutaneous, intraperitoneal,intranasal, enteral, topical, sublingual, or rectal means, with oral andintravenous routes being preferred. When administered orally, thecompounds can be administered as a liquid solution, powder (lyophilizedor otherwise), tablet, capsule or lozenge. Furthermore, oralformulations may include one or more of the present compounds incombination with one or more conventional pharmaceutical additive orexcipients that are typically used in the preparation of tablets,capsules, lozenges and other orally administrable forms. Whenadministered as an intravenous solution, the derivatives of the presentinvention can be admixed with conventional IV solutions to forminjectable aqueous or oily suspensions or solutions.

In accordance with one embodiment, the themisone derivatives of thepresent invention are combined with other known anesthetic agents toenhance the performance of such compounds and decrease the incidence ofnegative side effects. For example, compositions according to thepresent invention may comprise a themisone derivative and phencyclidinetype general anesthetic such as ketamine or tiletamine and theirpharmaceutically acceptable salts, as well as selegiline or one of itspharmaceutically acceptable salts, combined in a single pharmaceuticalcomposition for simultaneous administration, or presented separately foradministration in close succession. In the latter case, selegiline hasthe role of pre-anesthetic or restraining agent. Tiletamine is2-(ethylamino)-2-(2-thienyl)cyclohexanone. Ketamine is(+−)-2-(2-chlorophenyl)-2-methyl-aminocyclohexanone. Selegiline (−)-N,alpha-dimethyl-N-(2-propynyl) phenethylamine.

The present invention also provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of thethemisone derivatives of the present invention. In accordance with oneembodiment a kit is provided for anesthetizing a patient. In thisembodiment the kit may comprise one or more anesthetic agents of thepresent invention and as well as other known anesthetic agents andpre-anesthetic or restraining agents. These pharmaceuticals can bepackaged in a variety of containers, e.g., vials, tubes, microtiter wellplates, bottles, and the like. Preferably, the kits will also includeinstructions for use.

In one embodiment a composition comprising a themisone derivative of thepresent invention is used as a general anesthesia in mammals, includingboth human and domesticated animals. More particularly, compositionscomprising the present themisone derivative are administered eitherorally or parenterally to a mammalian species to induce anesthesia. Whenadministered orally, the compounds are administered as a liquidsolution, powder, tablet, capsule or lozenge. The compounds can be usedin combination with one or more conventional pharmaceutical additive orexcipients used in the preparation of tablets, capsules, lozenges andother orally administrable forms. When administered parenterally, andmore preferably by intravenous injection, the derivatives of the presentinvention can be admixed with saline solutions and/or conventional IVsolutions.

In accordance with one embodiment, a method is provided for inducinganesthesia in a human patient. The method comprises the steps ofadministering to the patient a composition comprising a compoundrepresented by a formula selected from the group consisting of

wherein R₁ is selected from the group consisting of H, halo, C₁–C₄haloalkyl, —NH₂, hydroxy, and C₁–C₄ alkoxy;

R₂, R₃ and R₄ are independently H or alkyl;

R₆, R₇ and R₈ are independently halo; and

n is an integer ranging from 0–4, and a pharmaceutically acceptablecarrier.

In one preferred embodiment the method of inducing anesthesia in amammalian species comprising administering a pharmaceutical compositioncomprising a compound of the general formula:

wherein R₁ is selected from the group consisting of H or halo and R₆, R₇and R₈ are independently H or halo, with the proviso that at least oneand more preferably two of R₆, R₇ and R₈ are halo. More preferably R₁ isF or Br and R₆, R₇ and R₈ are independently F or Cl.

In accordance with one embodiment, a method is provided for treating aneurological condition, including the treatment of seizures. The methodcomprises the steps of administering to a patient a compositioncomprising a compound represented by a formula selected from the groupconsisting of

wherein R₁ is selected from the group consisting of H, halo, C₁–C₄haloalkyl, —NH₂, hydroxy, and C₁–C₄ alkoxy;

R₂ and R₄ are independently H or alkyl;

R₁₀ and R₅ are independently H, alkyl, or R₁₀ and R₅ taken together, canform with the adjacent ring, an optionally substituted 5- or 6-memberedheterocyclic ring;

R₉ is optionally substituted aryl or haloalkyl; n is an integer rangingfrom 0–2; and R₁₃ is haloalkyl. More preferably, R₁ is H or halo, R₂ isH and n is 0.

In accordance with one embodiment the method of treating a neurologicalcondition comprises administering a composition comprising a compound ofthe general formula:

wherein R₁ is H or halo;

R₄ is H or alkyl;

R₁₀ and R₅ are independently H, alkyl, or R₁₀ and R₅ taken together, canform with the adjacent ring, an optionally substituted 5- or 6-memberedheterocyclic ring;

R₁₃ is haloalkyl; and

R₁₄ is C₁–C₁₂ alkyl. More preferably, R₁ is H or halo, R₄, R₅ and R₁₀are H and R₁₄ is C₄–C₆ alkyl. In one embodiment these compounds areadministered to a patient as a treatment for reducing the incidence andseverity of seizures.

In accordance with the present invention compositions comprising anatrolactamide derivative are administered to a patient to provideneuroprotection in systemic and neurological disease, includingneuropathic pain. The compounds can be administered prophylactically,acutely, subacutely, or chronically via the intravenous, oral or rectalroute. The compounds of the present invention are anticipated to haveactivity as analgesics, anti-arrhythmics, mood stabilizers,neuroprotectants and inhibitors of prostate cancer.

In accordance with one embodiment, the hydrogens of the 2-methyl groupsubstituent of themisone are substituted with halo groups to prevent theelimination reaction and formation of 2-phenyl-acrylamide. For example,the hydrogens can be replaced with fluorine to create3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide (17). Fluorine is anclassic mimic for hydrogen, with the two elements having similar Van derWaals radii, 1.20 and 1.35 angstroms, respectively.

Anticonvulsant testing of3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide (17) in rats revealedthe compounds have anesthetic activity at an oral ED₅₀ of 9 mg/kg andtoxicity at 300 mg/kg. Further testing in UVa's Department ofAnesthesiology revealed the fluorinated derivative lowered the minimumalveolar concentration (MAC) value of isoflurane (1.2% in O₂) by sixtypercent, with no hemodynamic effects. Furthermore, testing of3,3,3-Trifluoro-2-hydroxy-2-(4-fluoro-phenyl)-propionamide (39) revealedthis compound provided 3 out of 4 animals with a 100% reduction inIsoflurane MAC at 300 mg/kg. The tested animals exhibited surgicalanesthesia, the third stage of anesthesia displayed by general loss ofspinal reflexes and muscle tone. Themisone was later tested and found tohave no anesthetic activity. Other themisone compounds have now beentested and found to exhibit both anticonvulsant and anestheticactivities as described in the following examples.

Compound 39 also demonstrated activity as an anticonvulsant both in theMES and scMET assays (See Example 3). In particular, in phase I oral ratdata generated with MES, 4 out of 4 rats were protected using 30 mg/kgfor a duration of 2 hours. In phase I intraparentoneal data for MES 2out of 3 mice were protected at 100 mg/kg for a duration of 1 hour and 5out of 5 mice were protected at 100 mg/kg for a duration of 0.5 hours.Neurotoxicity revealed that seven of eight mice were unable to grasp rodat 100 mg/kg for a duration of 0.5 hours.

EXAMPLE 1

Structure Activity Relationship (SAR) of3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide Using Ligand BasedDesign

In accordance with one embodiment of the present invention, theformation of 2-phenyl-acrylamide is blocked by replacing the hydrogensof the 2-methyl group substituent of themisone with compounds thatprevent the elimination reaction. For example, the hydrogens can bereplaced with fluorine to create3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide (17).

Anticonvulsant testing of3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide (17) in rats revealedthat in addition to exhibiting anticonvulsant activity, this themisonederivative has anesthetic activity at an oral ED₅₀ of 9 mg/kg andtoxicity at 300 mg/kg. Themisone was later tested and found to have noanesthetic activity. Animals administered3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide (17) exhibited surgicalanesthesia, the third stage of anesthesia displayed by general loss ofspinal reflexes and muscle tone. Further testing in UVa's Department ofAnesthesiology revealed the fluorinated derivative lowered the minimumalveolar concentration (MAC) value of isoflurane (1.2% in O₂) by sixtypercent, with no hemodynamic effects. In general for compound 17investigation of structure to general anesthetic relationship revealedthat the phenyl ring conformation of 17 is important and thatpara-electron withdrawing groups increase the anesthetic activity of thecompound. In addition increased halogen size and saturation at theposition 3 carbon also increase anesthetic activity. A hydrogen bonddonor is also important at the position 2 carbon, but bulk is not welltolerated.

To investigate the activity of various3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionamide related compounds, thefollowing derivative compounds will be prepared:

It is anticipated that these derivatives will provide an orallyavailable general anesthetic that is capable of inducing anesthesiasmoothly and rapidly, allow rapid recovery, and pose a wide margin ofsafety (high therapeutic index). These compounds are also expected toexhibit dual anticonvulsant activity. Synthesis of the dualanticonvulsants and general anesthetics began with the hydroxyamides ofthe commerically available phenyl substituted trifluoro-methyl ketones.

Reaction conditions: a: TMSCN, TiCl₄, CH₂Cl₂; b: H₂O; c: 1,4-dioxane,conc. HCl, HCl gas.

Similarly, the synthetic scheme for preparing meta-F, para-Clderivatives is shown in scheme II, respectively:

Reaction conditions: a: TMSCN, ZnI₂, CH₂Cl₂; b: 15% HCl, THF; c:1,4-dioxane, conc. HCl, HCl gas.

Closed ring analogs of the lead compound were synthesized by the use ofTMS—CF₃ (see Scheme III). Several attempts had been made to synthesizethe compound with the use of tetrabutylammonium fluoride (TBAF). Thetrimethylsilyl ether intermediate was found to be very stable anddifficult to quench with varying amounts of acid. The exothermicreaction of a catalytic amount of KF, and saturated t-BuOK in THF, wasfound to produce the desired product, although in low yield withunprotected amides.

Reaction Conditions: a: TMS—CF3, KF, t-BuOK, THF; b: 15% HCl

N-trifluoroacetylpiperdine 25 was reacted with 0.8 equivalents of4-Bromoanisole to yield 26 (see Scheme IV). All other ketones can now besynthesized to yield all the remaining hydroxyamides with the use ofTMS—CN, followed by HCl gas.

Rxn Conditions: a: piperdine, Et₃N, Ether; b: 4-Bromoanisole, Mg, I₂,THF; c: NH₄Cl

Halogenation of general anesthetics stabilizes the compounds and reducesmetabolism. We hypothesized that changes in the haloform content couldhave an affect on potency, duration and hemodynamic acitivty. Thechlorinated cyanohydrin 28 was successfully made (see Scheme V),although several attempts to synthesize the hydroxyamide wereunsuccessful. Under acidic conditions such as HCl and HCl gas, or formicacid and HCl gas converted the cyanohydrin back to the starting ketone.Other unsuccessful attempts included K₂CO₃ and 30% H₂O₂, and UHP andK₂CO₃. A new synthetic scheme is now being evaluated starting with theacid chloride, trichloroacetyl chloride (see Scheme VI). The brominatedketone was made, although in low yield (see Scheme VII). Severalattempts to form the cyanohydrin, with the use of TMS—CN and variouscatalysts were unsuccessful. It is believed that steric hinderance playsa large role in the difficulty of synthesizing these two hydroxyamides.

Reaction Conditions: a: acetophenone, acetic acid, reflux, 8 hrs.; b:TMS—CN, THF, reflux, 12 hrs.; c: 15% HCl; d: conc. HCl, HCl gas; e:formic acid, HCl gas; f: K₂CO₃, 30% H₂O₂; g: UHP, K₂CO₃.

Reaction Conditions: a: KCN, 18-crown-6, CH₂Cl₂; b: DMSO, K₂CO₃, 30%H₂O₂; c: ZnPh₂

Reaction Conditions: a: Br₂, NaOH, H₂O, 1,4-dioxane, 0° C. to RT; b:TMS—CN, ZnI₂, CH₂Cl₂; c: TMS—CN, KCN, 18-crown-6, CH₂Cl₂.

200 mg of each compound are tested for general anesthesia activity.Testing is performed on rats to determine the percent reduction in theuse of isoflurane. Inhaled anesthetics still need to be utilized torapidly adjust the level of anesthesia. Since no single anesthetic iscapable of all four requirements for anesthesia, a combination isutilized. The rats were first anesthesized with isoflurane, intubated,ventilated and then a femoral line was inserted. After the rat had beenstable for 15 minutes, the initial minimum alveolar concentration (MAC)value was determined. Then, 60 mg/kg of drug was sonicated in 3 mL ofpeanut oil and injected (i.p.). After 30 minutes the second MAC valuewas determined post administration. Finally, after one hour the thirdMAC value was determined. At each MAC determination, a sample of bloodwas taken to determine pH, pCO₂, and pO₂. The results of the compoundstested to date are compared to the lead compound 17.

A classical comparison of log P and MAC reduction was investigated. Agraph representing the effects of log P on the biological activity ispresented in graphic form (See FIG. 1). The general anesthetic activityof compounds 20–23 and 36–43 were compared to lead compound 17 asrepresented in the graph (FIG. 1) and in Table 1. The partitioncoefficient, P, is a measure of the way the compound distributes itselfbetween octanol and water. The graph displays a general parabola shapewith an optimal log P value of approximately 1.5, since compounds 20 and42 were very toxic, despite their high activity. Compounds 20 and 42also had a low lethal dose of 300 mg/kg. Derivatives withpara-substituted phenol ring derivatives 21 and 39 were found to be veryactive, but also toxic at the same dosage. Therefore, meta-substitutedderivatives 20 will be the focus of future synthesize. Bulkysubstituents on the alcohol were also found to have low activity. Closedring analogs are active at lower levels but cause no hemodynamiceffects.

TABLE 1 MAC value of Isoflurane Percent at 60 mg/kg Reduction inHemodynamic Compound of compound* Isoflurane Effects Log P 17 0.65 46none 1.26 20 0.70 42 lowers blood 1.82 pressure 21 0.65 46 none 1.42 221.05 12.5 none 1.13 23 0.95 20.8 none 1.36 *1.2% isoflurane generates100% anesthesia; log P calculated using by Crippen's fragmentation: J.Chem. Inf. Comput. Sci., 27, 21(1987) in ChemDraw Ultra

EXAMPLE 2

The phenyl-substituted caprolactams have been found to be very activeanticonvulsants. Therefore, the —CF₃ moiety was added to the sevenmembered ring carpolactam (see Scheme VIII) and these compounds areanticipated to have activity as anticonvulsants. -Caprolactam is alphabrominated with bromine and phosphorus pentachloride. Formation of theenamine 31 is accomplished with 30 refluxed in piperdine for 6 hours.Cleavage of the enamine is done on a silica gel column eluted with ethylacetate. Due to the low yield of 32 the amide was protected before thereaction with TMS—CF₃. There were several unsuccessful attempts toprotect the amide, using benzyl bromide and various bases.

Reaction Conditions: a:Br₂, PCl₅, CHCl₃; b: piperdine, reflux, 6 hrs.;c: silica gel, EtOAc; d: TMS—CF₃

EXAMPLE 3

Anticonvulsant Properties of the Themisone Derivative Compounds

To investigate the anticonvulsant properties of the themisonederivatives, synthesis of the seven chain carbon hydroxyamides withsubstituted chlorine and methoxy groups on the phenyl ring were preparedin accordance with scheme IX. These derivatives were made asanticonvulsants and were not predicted to be active general anesthetics.

Reaction Conditions: a: 1-Bromoheptane, Mg, I₂, THF; b: 15% HCl; c:TMSCN, ZnI₂, CH₂ Cl₂; d: 15% HCl, THF; e: 1,4-dioxane, conc. HCl, HClgas.

300 mg of each compound was synthesized and sent to the Nationalinstitute of Health's Anticonvulsant Screening Project of theAntiepileptic Drug Discovery Program. NIH performs anticonvulsanttesting (oral and intraperitoneal, i.p.) on both mice and rats in phaseI trials. The grand mal model is conducted with a maximal electroshock(MES) test, where corneal electrode implants are primed with a drop ofelectrolyte solution and an electrical stimulus is delivered for 0.2second. The model examines the compounds' ability to stop the spread ofseizures. The petite mal model is conducted with a subcutaneouspentylenetetrazol seizure threshold (scMet) test. The animals areinjected with a convulsant dose of pentylenetetrazol at the peak effecttime of the compound. This model measures the compounds' threshold forseizures. A toxicity test (TOX) is performed where the animals walk on aspinning rod for varying lengths of time to check for the loss ofrighting reflex or other toxic effects. Phase I evaluation at 30, 100and 300 mg/kg of test compounds has resulted in several newly discoveredactive anticonvulsants (See FIGS. 2–5).

One important aspect of central nervous system drug delivery is braindistribution. Derivatives of phenytoin were designed and synthesizedwith fluorine tags (see scheme IX). The compounds were tested using thekindling model to access their anticonvulsant activity. Rats with theinjected drugs will then be exposed to ¹⁹F magnetic resonance imaging(MRI) to study the drug distribution in the brain of a known compound.The model will then be used as a model to test the active fluorinatedcompounds.

Reaction Conditions: a: KCN, (NH4)2CO3, 50% EtOH, 65° C., 24 hrs.

TABLE 2 Anticonvulsant Testing (NIH) Mice I.P. Administration Cmp CmpCmp Cmp Cmp Cmp 20 20 21 21 23 23 Dose Time Time Time Time Time Time(mg/ (0.5 (4.0 (0.5 (4.0 (0.5 (4.0 Test kg) hours) hours) hours) hours)hours) hours) MES 30  0/1^(a) 0/1 0/1 0/1 0/1 0/1 MES 100 3/3 3/3 0/31/3 3/3 0/3 MES 300 0/0 1/1 n/a n/a 1/1 1/1 SCMET 30 2/5 0/1 0/1 0/1 1/50/1 SCMET 100 1/1 1/1 4/4 1/1 0/1 0/1 SCMET 300 n/a n/a 0/0 1/1 1/1 1/1TOX 30 0/4 0/2 0/4 0/2 0/4 0/2 TOX 100 6/8 0/4 6/8 3/4 1/8 0/4 TOX 300 4/4^(b)  1/1^(c)  4/4^(b)  1/1^(c)  4/4^(c) 1/2 ^(a)0/1 refers tonumber of animals protected/number of animals tested ^(b)loss ofrighting reflex and one death ^(c)loss of righting reflex

TABLE 3 Anticonvulsant Testing (NIH) Rat Oral Administration-Compound 21Dose Test (mg/kg) 0.25 hrs. 0.5 hrs. 1.0 hrs. 2.0 hrs. 4.0 hrs. MES 301/4 1/4 1/4 1/4 1/4 TOX 30 0/4 0/4 0/4 0/4 0/4

TABLE 4 Anticonvulsant Testing (NIH) Rat Oral Administration-Compound 23Dose Test (mg/kg) 0.25 hrs. 0.5 hrs. 1.0 hrs. 2.0 hrs. 4.0 hrs. MES 302/4 1/4 2/4 2/4 2/4 TOX 30 0/4 0/4 0/4 0/4 0/4

EXAMPLE 4

Additional Synthetic Schemes

Synthesized themisone derivatives:

1. A method for inducing anesthesia in a mammalian species said methodcomprising the steps of administering a composition comprising acompound represented by the formula:

wherein R₁ is selected from the group consisting of H, halo, C₁–C₄haloalkyl, —NH₂, hydroxy, and C₁–C₄ alkoxy; R₂, R₃ and R₄ areindependently H or alkyl; R₆, R₇ and R₈ are independently halo; and n isan integer ranging from 0–4 and a pharmaceutically acceptable carrier.2. The method of claim 1 wherein said compound has the generalstructure:

wherein R₁ is H or halo; and R₆, R₇ and R₈ are independently selectedfrom the group consisting of F, Cl and Br.
 3. A method for treating aneurological condition said method comprising the steps of administeringa composition comprising a compound represented by the formula:

wherein R₁ is H or halo; R₄ is H or alkyl; R₁₀ and R₅ are independentlyH, alkyl, or R₁₀ and R₅ taken together, can form with the adjacent ring,an optionally substituted 5- or 6-membered heterocyclic ring; R₁₃ ishaloalkyl; and R₁₄ is C₁–C₁₂ alkyl.
 4. The method of claim 3 wherein R₁is H or halo, R₄, R₅ and R₁₀ are H and R₁₄ is C₄–C₆ alkyl.